They test how it degrades under stress to determine a maximum viability under perfectly stable conditions. They are not accounting for the typical medicine storage places: a bathroom cabinet where the temperature and humidity will vary wildly within a matter of minutes, a cool, damp fridge, or even the reading table next to your bed-- constantly exposed to UV light from the windows.
I'm relaying this secondhand from a former FDA contractor, but I can only surmise that for a company with the litagative risk level that any pharmaceutical entity incurs, the old adage of "Better Safe Than Sorry" is a major part of the story that's missing here.
It's not any more efficient to stockpile drugs, and it doesn't make sense to do so, as your need for prescription drugs is likely not going to be multiple years.
Develop an "indicator pill" that changes color at the same rate as an individual medication.
It would be in (or part of) the bottle with the other pills, and be customizable to react to humidity, temperature and time in the same way as the particular medication.
How feasible would that be for thousands of different drugs with hundreds of thousands of different formulations and chemical compositions and various storage factors ?
Do you mean that varying conditions make medicines last longer? You can't mean that medicines would last much longer if stored in perfect conditions, because that's not expiring "earlier than they should", it's expiring exactly on time for the poor conditions they are kept in.
Can you clarify?
Most chemical processes happen faster with a higher temperature. Some drugs decay into harmful substances (e.g. Aspirin).
Other factors, such as humidity or UV, may play a part as well.
Rather than testing every permutation of storage conditions over time, manufacturers put a safety margin. Individual consumers aren't in a position to remember exactly how they treated any given container of pills. Even if the manufacturer knew how a given sequence of storage practices affected their drug, nobody would be the wiser.
Well, it keeps out humidity, and might prevent air-exposure effects. It won't prevent heat effects and some other environmental effects.
Also, quite a lot are sold in bottles of pills or other non-blister-pack forms.
I remember vaguely having seen pills in bottles maybe 20 or 30 years ago. Again this is for France, I know that e.g. in the US one gets refills.
Which by the way I find great because the waste of pills is tremendous. It would have been much better to get the specific number prescribed.
Over here, benadryl is the main over-the-counter drug I see in blister packs. They say it's to slow down the meth cookers.
I'm a long time pollen allergy sufferer living in the hell that is South Florida. I know my allergy meds.
In Australia the only thing in bottles are vitamins and similar, though it is possible to get small bottles.
* acetaminophen / paracetamol
The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.
Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world.
Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans.
Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population.
Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo.
The dose we take is not a "BEST GUESS"
It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo.
It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag).
Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587
https://www.ncbi.nlm.nih.gov/pubmed/14714120 No difference in response between people taking 20 mg prozac daily vs. every third day.
Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.
You are the one who is completely wrong.
The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work
Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through?
It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
Hence the 'The dose we take is not a "BEST GUESS"' (emphasis mine). Unless you're a lab animal or a person in a clinical trial, the does you take is the end result of lots of money spent on first figuring out maximum safe dosages (Phase 1) to prescribing guidelines that doctors are taught (Phase 3).
Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination. The problem is that many psychiatrists don't have the time (due to insurance billing practices) or the patience to do the work but any decent psychiatrist will tell you that recommended doses for antidepressants are just a safe starting point for most patients, not the dosage that they will eventually find most effective.
For the record, I have worked in the pharmaceutical industry on pre-clinical drug development and Phase 1-3 marketing applications and the GP's description is largely accurate whereas you seem to have a chip on your shoulder. I wouldn't trust a single book about the drug development process that wasn't heavily influenced by the pharmaceutical industry in one way or another just like I wouldn't trust anyone without semiconductor industry experience when talking about Intel's cutting edge fabrication processes.
How does one accomplish this absent trial and error?
This fact undermines the entirety of your argument.
"Best guess" is exactly what they do.
Please take your clearly ignorant bias and anti-pharma prejudice somewhere else - you have no idea what you're talking about.
We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works.
Pedantic but important difference.
I have a prescription for dexamphetamine, but I don't use/need it a lot, so I have some bottles left that are a bit old--not past the expiration date, which appears to be slightly less than 3 years (after the date of the recipe), on the bottle I'm currently looking at. So I was curious about the amphetamines in particular, and if it's just efficacy deteriorating a bit that's fine, because in my personal experience the effect (which is quickly and clearly noticeable) varies easily by 25% already, depending on so many other factors (like what/how much I eat, how well I slept, stuff like that).
10-25 percent of....what?
Wrong. Therapeutic ratio, not dosage.
LSD's therapeutic index is unknown because its LD50 has never been established in humans or monkeys and you can't extrapolate from non-primate animals to humans (for example, rats can handle a dose of fentanyl that is a thousand times higher per kg than monkeys can, which is where many of our LD50 estimates come from).
I was going to post something long about LSD but it turns out I am just wrong. So thanks twice, and have my upvote.
Likewise, in a clinical setting (i.e, with a trained anesthesiologist in fentanyl's case), the dose at which 50% of patients die from a given drug is usually much higher because trained professionals can quickly receive feedback by monitoring the patient's symptoms and apply drugs or medical devices to keep them alive well beyond what could kill someone on the street.
The therapeutic index is the ratio of the therapeutic dose to the dose at which the drug starts becoming toxic in 50% of the sample. I repeat, for the third time, I was not talking about toxicity. We are discussing drug expiration dates and you will not experience toxicity from a drug that has been degraded over time to a dosage lower than the one you were prescribed, except in extremely rare circumstances. A drug's therapeutic index is entirely irrelevant to what I am talking about - I don't know how I can make that any more clear.
It also does not follow that because a drug is active in small amounts, i.e. micrograms instead of milligrams, that a small percent change in the dosage will be more important. Full stop illogical, and also not true in practice.
So yes, I'm not a doctor and I don't know the jargon. And when I read your comment I forgot the article was about expiration dates, i.e. percent decrease. And yet you were still wrong on that particular point.
In my personal experience (a decade of Burning man), when you do have a known concentration of liquid LSD (measured with an LCMS) that you carefully handle, store, and dilute for dosages, 100 mcg and 125 mcg can mean the difference between a good trip and a bad one in at least a tenth of my sample size and can drastically change the intensity of hallucinations (going from zero to fractal visuals to aliens) in a good quarter - not to mention the effect on the body high and introspection. If you're buying tabs, the chances that you are even close to the original concentration falls rapidly the further removed you are from the original source. Most people can't tell the difference between a 100mcg and 125mcg tab because those dosages are exaggerated and many people feel stereotypical effects at lower dosages. You can easily test this by eating a significant fraction of a blotter: you are extremely unlikely to experience the effects described by the literature of 50 ng/mL blood concentrations even if you're lucky enough to get to 5 ng/mL effects with a few tabs.
Saying that a 25% change is more significant for more potent drugs is illogical on the face of it, because a % is a dimensionless quantity. If there is some subtle reason why this trend exists I'd love to hear it.
Actually, the reverse is illogical because few biochemical systems have linear responses, especially when you're talking about something as complicated as the neurotransmitter systems that LSD effects. Potency depends on two factors: the affinity of the drug, or how well it binds to its target receptors, and efficacy, or the relationship between the concentration of the drug (and second order neurotransmitters) and the ability of the receptors to initiate a cellular response. Neither of those two factors are linear and they both change as the concentrations of the drug and its byproducts change. As neuron receptors are activated by LSD, they cause cells to release a flood of other neurotransmitters at varying concentrations (dependent on LSD concentration and individual brain chemistry) that start interacting in complex ways like preventing the LSD and other neurotransmitters from binding as effectively (lowering their affinity), potentiating the cellular response (increasing its strength aka increasing efficacy), or building tolerance (lowering efficacy due to exposure). Each receptor and neurotransmitter pair behaves differently. Neurotransmitters in general can't activate cellular responses before they are above a threshold potential that causes the neuron to react, after which the cellular response is never linear. A 2x increase in concentration will rarely achieve a 2x response unless it falls in a small range where the curve is mostly linear, and even then the complex interactions between all of the neurotransmitters will usually compound into a nonlinear response anyway.
These interactions get so complicated, for example, that you get many cases were an opiate A, which is technically 10x more potent than an opiate B, can actually be less potent at treating mild pain because it has a steep response curve that doesn't ramp up until a certain dose. 10mcg/kg of opiate B might be 10x stronger than 10mcg/kg of opiate A (which could be too low to even feel the painkilling effects of opiate A) but once you hit 50mcg/kg concentrations, opiate A might be 10x more potent than opiate B, whose effects plateau with doses higher than 20mcg/kg. Potency is typically expressed as the [A]50 - the concentration of the drug at which you reach 50% of the maximum effect, which depends on the therapeutic effect you're looking for. So in this example, the [A]50 of opiate A in mild pain scenarios can be 25mcg/kg versus opiate B's 7 mcg/kg while with severe pain, the [A]50 of opiate B can be above its LD50 and opiate A's can be 30 mcg/kg because from 25 to 30 mcg/kg opiate A has an exponential response curve. Like I said, it's very complicated and when measuring potency, you're actually measuring the effects of concentration on "arbitrary units," which could be something concrete like a chemo drug's effectiveness at killing cancer cells or something subjective like pain relief. When it's the latter, especially, potency has a very specific meaning in pharmacology that is very different from how the word is used colloquially.
Please don't talk about pharmacology. Period. You don't know what you are talking about and someone might make the mistake of believing otherwise and do something dangerous.
> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical.
As in, typical dosages for fent or LSD are on the order of micrograms, so we expect them to be sensitive to a 25% change, for other drugs where a typical dose is measured in mg or grams, 25% is less likely to be a big deal, etc. This is the only way to interpret what you wrote, and it doesn't make sense. No such trend exists. None of the "basic facts" which you "explained" above (which I already knew) go anywhere near supporting this assertion.
Put another way, if you know the [A]50 you know one point on the dose-response curve, but in general that tells you nothing about the slope or shape of the curve near that point.
Judging from your comment history, you are not an actual doctor or biomed researcher, just a programmer in that industry. Which makes your teeth-gnashing about what an authority you are a tad less persuasive.
> Twelve of the 14 drug compounds tested (86%) were present in concentrations at least 90% of the labeled amounts, the generally recognized minimum acceptable potency. Three of these compounds were present at greater than 110% of the labeled content. Two compounds (aspirin and amphetamine) were present in amounts of less than 90% of labeled content. One compound (phenacetin) was present at greater than 90% of labeled amounts from 1 medication tested, but less than 90% in another medication that contained that drug.
http://jamanetwork.com/journals/jamainternalmedicine/fullart...
Sounds like maybe concentrations are allowed to vary a bit from the label at manufacturing time? Not sure, maybe someone who knows more can comment.
Depending on necessity and value they can typically engineer more precision, but it gets very expensive very fast.
Relax, this is the real world, not a computer based series of 0s and 1s. Any such compound begins drifting off from the original specs as soon as it leaves the factory - and in a very real sense it's not exactly at 100% at any time post the moment of manufacture. The question is what kind of deviation can be tolerated.
The world of logic is built on the shifting ground of reality. Only redundancy and checksums keep it from crashing down in compounded errors.
There was a time in my life where our family lived dollar to dollar and skipped medical care due to cost. We would easily settle for 90% efficacy.
Several of the drugs they tested were > 100%, so it seems reasonable to assume that a lot of this is due to variation in manufacturing rather than to the drug degrading.
producing powerful physical or chemical effects. ( http://www.dictionary.com/browse/potent )
chemically or medicinally effective ( https://www.merriam-webster.com/dictionary/potent )
exerting or capable of exerting strong physiological or chemical effects ( http://www.thefreedictionary.com/Potent )
At the end of the day, there's no really reliable way to speed up time, and it would be a waste of time to add 10 years to a drug development timeline just so you can leave it on a shelf for 10 years to test if it still works.
And yeah, we could probably go through and retroactively test some Ibuprofin, but also remember that these drugs are repackaged / reformulated slightly every couple years for various reasons, and without a lot of legal protections, no company will consider it worth it to guess about drug lifetime.
...or in case of tablets that come in 2x/4x the dose and you need to cut them in half/four pieces, the precision of your cut and amount of tablet dust that is lost.
It's a lot of guess work.
For many drugs a 2% difference is probably unnoticeable. Why are Ibuprofen pills 200mg? Because it's a nice round number that happens to work for many people. If I have a headache I often break the 200mg pill and only take half of it. It still does the job fine for me with fewer side effects.
So if a 110lb wife gets the same dosage as a 200lb husband, how on earth would even a 20% difference in dosage amount make a big difference?
2% can only be done in fantasyland, like in a hospital you and the medicine are both closely weighed and administered.
How do you know that your doctor didn't take your weight into consideration when selecting the dose for a prescription medicine?
OTC drugs are often generally provided at a dose that should be safe for most adults, but may be significantly different in effectiveness based on weight.
Why is this a "surely"? On a scale of 100%, 2% is 2% because it's not hugely significant.
Disclaimer: this is conjecture.
To investigate how a drug breaks down over a ten-year timespan, you'd need to do at least one ten-year study of the drug. That seems difficult to justify.
It seems like it would be a good long term investment for a group of hospitals to partner together and begin a systematic study of the actual lifetimes of drugs. Instead of destroying all expired drugs they could send off samples to a lab for testing. They could even intentionally keep expired drugs in an off-limits area for 1, 2, 3 years past their expiration dates to gather more information. With enough hospitals participating they could gather a significant amount of data without any one hospital shouldering all of the burden. Once there is enough evidence that a particular drug is still potent the FDA could extend the allowed shelf life. This would save the hospitals money over time since they could stop paying to dispose of and replace as many expired drugs. It would also provide a general benefit to the public since people would have solid scientific evidence for the actual effective lifetime for particular drugs. This would include poison control centers, the hospitals themselves, etc. that would be able to better handle cases where someone has already taken an expired drug.
Of course an alternate way would be to require the drug companies to accept returns from hospitals of small amounts of expired drugs that they would then be responsible for testing and providing the data to the FDA. Limiting the returns to large institutions would keep the costs down (reducing push-back from the pharma companies).
Since the % is of labelled strength, it might still be “as potent as when manufactured” if the drug was at less than labelled strength when manufactured, though that, too, would be a serious issue.
What kind of reporting is this? Anything less than 100% is not "as potent as when manufactured", and the sentence implies some of those dozen weren't close to 100%.
> The idea that drugs expire on specified dates goes back at least a half-century, when the FDA began requiring manufacturers to add this information to the label. The time limits allow the agency to ensure medications work safely and effectively for patients. To determine a new drug’s shelf life, its maker zaps it with intense heat and soaks it with moisture to see how it degrades under stress. It also checks how it breaks down over time. The drug company then proposes an expiration date to the FDA, which reviews the data to ensure it supports the date and approves it. Despite the difference in drugs’ makeup, most “expire” after two or three years.
That seems to be the problem. There was a procedure in place to set expiration dates scientifically, and it was ignored for some reason, limiting the legal shelf life of even the most stable compounds to a few years.